Controlled release of an active agent; i.e., release of the active agent over a period of time, has been a source for considerable research effort over the past twenty to thirty years. Exemplary of systems that utilize controlled release of an active agent are microcapsules containing medicaments as are illustrated in U.S. Pat. No. 3,242,051 and U.S. Pat. No. 3,041,289. Substantially inert plastic matrices containing an active agent such as a pesticide dissolved or dispersed therein as are illustrated by U.S. Pat. No. 3,590,119, U.S. Pat. No. 3,639,583, and U.S. Pat. No. 4,012,221, exemplify yet another class of controlled release system.
Several materials, which in the presence of water adhere to the skin and/or mucus membranes, have been used by themselves or in conjunction with one or more active agents to treat various pathological conditions. Exemplary of such materials are the complex of sulfated sucrose and aluminum hydroxide known generically as sucralfate and available under the trademark CARAFATE.RTM. from Marion Laboratories, Inc. of Kansas City, Mo. Sucralfate is used alone or in conjunction with an antacid to treat duodenal ulcers. Another adherent material, designed for use in the buccal cavity, is a combination of gelatin, pectin and sodium carboxymethylcellulose in a plasticized hydrocarbon gel available under the trademark ORABASE.RTM. from Hoyt Laboratories Division of Colgate-Palmolive Co. of Needham, Mass. A mucosal adherent ointment based upon partly neutralized polymethacrylic acid methyl ester was recently reported by Bremecher et al., Arzneim.-Forsch./Drug Res., 33, 591 (1983). That ointment was reported to show a pseudoplastic quality without any thixotropic effect, good mucosal adhesion and no local irritation.
A sustained release compressed tablet is described in U.S. Pat. No. 3,065,143. The tablet is reported to contain a medicinal agent and a hydrophilic gum that hydrates rapidly and swells in aqueous fluids at body temperature. Several naturally occuring and synthetic gums are said to be useful. Particularly useful gums disclosed include hydroxypropyl methyl cellulose ethers, sodium carboxy methyl cellulose, a material described as carboxy polymethylene, and mixtures thereof.
Delayed release pharmaceuticals are also disclosed in U.S. Pat. No. 3,074,852. The compositions of this patent are disclosed to contain a medicinal component and a polymer carrier. The polymer carrier is disclosed as being a polymer of U.S. Pat. No. 2,798,053, prepared by polymerization of 0.75 to 2 percent by weight polyalkenyl polyether as cross-linking agent with acrylic acid, or its equivalent.
The polymerization is reported to be carried out in a hydrocarbon diluent with a free radical catalyst. The polymer of particular interest in U.S. Pat. No. 3,074,852 is said to be in acid form, and is more particularly described in U.S. Pat. No. 2,909,462, which patent further describes its polymers as being agglomerated by steam action. That particularly described polymer is reported to be the material sold as CARBOPOL.RTM. 934 by B. F. Goodrich Chemical Company.
U.S. Pat. No. 3,330,729 discloses tablets that contain a basic, pharmaceutically acceptable calcium or magnesium salt such as magnesium oxide, calcium oxide or calcium hydroxide admixed with a medicament and a cross-linked acrylic acid polymer. The cross-linked polymer utilized in those tablets is said to be described in U.S. Pat. No. 2,798,053, and contains acrylic acid cross-linked with about 0.75 to about 2 percent by weight of the polymer of a copolymerized polyalkenyl polyether. Exemplary polyalkenyl polyethers are disclosed as polyallyl sucrose or polyallyl pentaerythritol that are said to desirably contain an average of at least 3 allyl groups per molecule, the allyl groups being bonded by ether linkages. The exemplary, cross-linked polymer is again said to be CARBOPOL.RTM. 934.
U.S. Pat. No. 4,327,725 discloses an osmotic device that includes a semi-permeable wall surrounding a compartment housing (a) an agent (e.g., a drug) that is insoluble to very soluble in aqueous and biological fluids, and (b) a layer of a fluid, swellable, hydrogel. A large number of hydrogels are disclosed including neutral, anionic and cationic materials. The hydrogel is said to function in this device by imbibing an aqueous fluid, swelling, and thereby exerting a force against the solution or suspension of the agent, whereby the agent is dispensed through the semi-permeable wall.
A controlled release system based on a neutral hydrogel of a polymer of ethylene glycol methacrylate or similar monomer cross-linked sufficiently to make the polymer insoluble is disclosed in U.S. Pat. No. 3,551,556 Example 8 of that patent also discloses an acid-containing hydrogel prepared by the copolymerization of methacrylic acid and maleic anhydride to form what appears to be a linear, noncross-linked polymer. Drug concentration from that hydrogel delivery system was reported to soon reach a maximum and then decrease according to a flat, logarithmic curve.
Drug-dispensing films are disclosed in U.S. Pat. No. 3,641,237. The films of that patent are disclosed to be prepared by polymerization of lower alkoxy lower alkyl acrylates and methacrylates along with a 0-40 percent of a hydrophilic acrylic monomer in the presence of a cross-linking agent. Various monomers are disclosed as useful for the 0-40 percent co-monomers, including hydroxyalkyl acrylates and methacrylates, salts of alpha,beta-unsaturated organic acids and strong acid salts of polymerizable ethylenically unsaturated amine-containing monomers.
European Patent Office Publication No. A10 043 319 discloses copolymers capable of absorbing and progressively liberating pharmaceutically active substances. The useful copolymers are disclosed to contain about 30 to 80 percent acrylate or methacrylate alkyl monoester, about 5 to 68 percent acrylic or methacrylic acid and about 2 to about 15 percent of a bi- or tri-functional acrylate or methacrylate ester. Exemplary bi-functional ester cross-linking agents are ethylene and polyethylene glycol diacrylates. Trimethylolpropane triacrylate and triethylolpropane trimethacrylate are exemplarly tri-functional esters.
U.S. Pat. No. 4,226,848 discloses a composition for adhering a pharmaceutical preparation to the mucosa of the oral or nasal cavities. The composition disclosed contains a water-swellable and mucosa-adherent polymeric matrix comprising (a) about 50 to about 95 percent by weight of a cellulose ether and (b) about 50 to about 5 percent by weight of a homo- or copolymer of acrylic acid or a pharmaceutically acceptable salt thereof, with a pharmaceutically effective amount of a medicament dispersed therein.
It is stated in that patent that when either material of the adherent composition is used singly in producing a pharmaceutical preparation, the resulting preparation is unsuitable as a slow-releasing preparation because it does not adhere to the mucosa of the oral or nasal cavity or even when it adheres, it is relatively rapidly, disintegrated, dispersed or dissolved by the saliva or other secretions. The specified ratio of the two polymers that form the polymeric matrix is reported to be essentially required in order for the slow-releasing preparation disclosed in that patent not to cause whitening of the mucosa and to release the medicament at a controlled rate. It is further reported that when the polyacrylic acid or salt portion of that composition is present at greater than about 50 percent by weight, the preparation irritates the mucosa, and causes whitening of the mucosa and the marked occurance of blisters thereon.
The polyacrylic acid or salt portion of the preparation of U.S. Pat. No. 4,226,848 is also described as being water-soluble or water-swellable, but is further described as having a desired, specific range of viscosities at a concentration of 0.2 percent by weight in water. Thus, if that polymer is not truly soluble in water, it is dispersible to at least a sufficient extent to obtain the desired viscosity. An exemplary acrylic acid polymer disclosed therein is the lightly cross-linked acrylic acid-allyl sucrose copolymer available under the trademark CARBOPOL.RTM. 934 from B. F. Goodrich Chemical Co., which is said to form a high viscosity gel-like dispersion in water.